The present invention is concerned with benzimidazoles and imidazopyridines having antiviral activity, in particular, they have an inhibitory activity on the replication of the respiratory syncytial virus. It further concerns their preparation and compositions comprising them, as well as their use as a medicine.
Human RSV or Respiratory Syncytial Virus is a large RNA virus, member of the family of Paramyxoviridae, subfamily pneumovirinae together with bovine RSV virus. Human RSV is responsible for a spectrum of respiratory tract diseases in people of all ages throughout the world. It is the major cause of lower respiratory tract illness during infancy and childhood. Over half of all infants encounter RSV in their first year of life, and almost all within their first two years. The infection in young children can cause lung damage that persists for years and may contribute to chronic lung disease in later life (chronic wheezing, asthma). Older children and adults often suffer from a (bad) common cold upon RSV infection. In old age, susceptibility again increases, and RSV has been implicated in a number of outbreaks of pneumonia in the aged resulting in significant mortality.
Infection with a virus from a given subgroup does not protect against a subsequent infection with an RSV isolate from the same subgroup in the following winter season. Re-infection with RSV is thus common, despite the existence of only two subtypes, A and B.
Today only three drugs have been approved for use against RSV infection. Ribavirin, a nucleoside analogue, provides an aerosol treatment for serious RSV infection in hospitalized children. The aerosol route of administration, the toxicity (risk of teratogenicity), the cost and the highly variable efficacy limit its use. The other two drugs, RespiGam(copyright) and palivizumab, polyclonal and monoclonal antibody immunostimulants, are intended to be used in a preventive way.
Other attempts to develop a safe and effective RSV vaccine have all met with failure thus far. Inactivated vaccines failed to protect against disease, and in fact in some cases enhanced disease during subsequent infection. Life attenuated vaccines have been tried with limited success. Clearly there is a need for an efficacious non-toxic and easy to administer drug against RSV replication. EP-A-0,005,138, EP-A-0,099,139, EP-A-0,145,037, EP-A-0,144,101, EP-A-0,151,826, BP-A-0,151,824, EP-A-0,232,937, EP-A-0,295,742, EP 0,297,661, EP-A-0,307,014, WO 92 01697 describe benzimidazole and imidazopyridines substituted piperidine and piperazine derivatives as antihistaminics, antiallergics or serotonine antagonists.
The present invention concerns the compounds of formula (I) 
their prodrugs, N-oxides, addition salts, quaternary amines, metal complexes and stereochemically isomeric forms wherein
xe2x80x94a1xe2x95x90a2xe2x80x94a3xe2x95x90a4xe2x80x94 represents a bivalent radical of formula
xe2x80x94CHxe2x95x90CHxe2x80x94CHxe2x95x90CHxe2x80x94xe2x80x83xe2x80x83(a-1);
xe2x80x94Nxe2x95x90CHxe2x80x94CHxe2x95x90CHxe2x80x94xe2x80x83xe2x80x83(a-2);
xe2x80x94CHxe2x95x90Nxe2x80x94CHxe2x95x90CHxe2x80x94xe2x80x83xe2x80x83(a-3);
xe2x80x94CHxe2x95x90CHxe2x80x94Nxe2x95x90CHxe2x80x94(a-4); or
CHxe2x95x90CHxe2x80x94CHxe2x95x90Nxe2x80x94xe2x80x83xe2x80x83(a-5);
wherein each hydrogen atom in the radicals (a-1), (a-2), (a-3), (a-4) and (a-5) may optionally be replaced by halo, C1-6alkyl, nitro, amino, hydroxy, C1-6-alkyl-oxy, polyhaloC1-6alkyl, carboxyl, aminoC1-6alkyl, mono- or di(C1-4alkyl)-aminoC1-6alkyl, C1-6alkyloxycarbonyl, hydroxyC1-6alkyl, or a radical of formula 
xe2x80x83wherein xe2x95x90Z is xe2x95x90O, xe2x95x90CHxe2x80x94(xe2x95x90O)xe2x80x94NR5aR5b, xe2x95x90CH2, xe2x95x90CHxe2x80x94C1-6alkyl, xe2x95x90Nxe2x80x94OH or xe2x95x90Nxe2x80x94Oxe2x80x94C1-6alkyl;
Q is a radical of formula 
wherein Alk is C1-6alkanediyl;
Y1 is a bivalent radical of formula xe2x80x94NR2xe2x80x94 or xe2x80x94CH(NR2R4)xe2x80x94;
X1 is NR4, S, S(xe2x95x90O), S(xe2x95x90O)2, O, CH2, C(xe2x95x90O), C(xe2x95x90CH2), CH(OH), CH(CH3),
CH(OCH3), CH(SCH3), CH(NR5aR5b), CH2xe2x80x94NR4 or NR4xe2x80x94CH2;
X2 is a direct bond, CH2, C(xe2x95x90O), NR4, C1-4alkyl-NR4, R4xe2x80x94C1-4alkyl;
t is 2, 3, 4 or 5;
u is 1, 2, 3,4 or 5;
vis 2or 3; and
whereby each hydrogen atom in Alk and the carbocycles and the heterocycles defined in radicals (b-3), (b-4), (b-5) (b-6), (b-7) and (b-8) may optionally be replaced by R3; with the proviso that when R3 is hydroxy or C1-6alkyloxy, then R3 can not replace a hydrogen atom in the xcex1 position relative to a nitrogen atom;
G is C1-10alkanediyl substituted with one or more hydroxy, C1-6alkyloxy, arylC1-6alkyloxy, C1-6akylthio, arylC1-6alkylthio, HO(xe2x80x94CH2xe2x80x94CH2xe2x80x94O)nxe2x80x94, C1-6alkyloxy-(xe2x80x94CH2xe2x80x94CH2xe2x80x94O)nxe2x80x94 or arylC1-6alkyloxy(xe2x80x94CH2CH2xe2x80x94O)nxe2x80x94;
R1 is a monocyclic heterocycle or aryl; said heterocycle being selected from piperidinyl, piperazinyl, pyridyl, pyrazinyl, pyridazinyl, pyrimidinyl, furanyl, tetrahydrofuranyl, thienyl, pyrrolyl, thiazolyl, oxazolyl, imidazolyl, isothiazolyl, pyrazolyl, isoxazolyl, oxadiazolyl; and each heterocycle may optionally be substituted with 1 or where possible more, such as 2, 3 or 4, substituents selected from halo, hydroxy, amino, cyano, carboxy, C1-6alkyl , C1-6alkyloxy, C1-6alkylthio, C1-6alkyloxyC1-6alkyl, aryl, arylC1-6alkyl, arylC1-6akyloxy, hydroxyC1-6alkyl, mono- or di(C1-6alkyl)amino, mono- or di(C1-6alkyl)aminoC1-6alkyl, polyhaloC1-6alkyl, C1-6alkylcarbonylamino, C1-6alkyl-SO2xe2x80x94NR5cxe2x80x94, aryl-SO2NR5cxe2x80x94, C1-6alkyloxycarbonyl, xe2x80x94(xe2x95x90O)xe2x80x94NR5cR5d, HO(xe2x80x94CH2xe2x80x94CH2xe2x80x94O)nxe2x80x94, halo(xe2x80x94CH2xe2x80x94CH2xe2x80x94O)nxe2x80x94, C1-6alkyloxy(xe2x80x94CH2CH2xe2x80x94O)nxe2x80x94, alylC1-6alkyloxy(xe2x80x94CH2xe2x80x94CH2xe2x80x94O)nxe2x80x94 and mono- or di(C1-6alkyl)amino(xe2x80x94CH2xe2x80x94CH2xe2x80x94O)nxe2x80x94; each n independently is 1, 2, 3 or 4;
R2 is hydrogen, formyl, C1-6alkylcarbonyl, Hetcarbonyl, pyrrolidinyl, piperidinyl, homopiperidinyl, C3-7cycyoalkyl substituted with N(R6)2, or C1-10alkyl substituted with N(R6)2 and optionally with a second, third or fourth substituent selected from amino, hydroxy, C3-7cycloalkyl, C2-5alkanediyl, piperidinyl, mono- or di(C1-6alkyl)amino, C1-6alkylcarbonylamino, aryl and aryloxy;
R3 is hydrogen, hydroxy, C1-6alkyl, C1-6alkyloxy, arylC1-6alkyl or arylC1-6alkyloxy;
R4 is hydrogen, C1-6alkyl or arylC1-6alkyl;
R5a, R5b, R5c and R5d each independently are hydrogen or C1-6akyl; or
R5a and R5b, or R5c and R5d taken together form a bivalent radical of formula xe2x80x94(CH2)sxe2x80x94 wherein s is 4 or 5;
R6 is hydrogen, C1-4alkyl, formyl, hydroxyC1-6akyl, C1-6alkylcarbonyl or C1-6alkyloxycarbonyl;
aryl is phenyl or phenyl substituted with 1 or more, such as 2, 3 or 4, substituents selected from halo, hydroxy, C1-6alkyl, hydroxyC1-6alkyl, polyhaloC1-6alkyl, and C1-6alkyloxy;
Het is pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl.
The term prodrug as used throughout this text means the pharmacologically acceptable derivatives, e.g. esters and amides, such that the resulting biotransformation product of the derivative is the active drug as defined in the compounds of formula (I). The reference by Goodman and Gilman (The Pharmacological Basis of Therapeutics, 8th ed., McGraw-Hill, Int. Ed. 1992, xe2x80x9cBiotransformation of Drugsxe2x80x9d, p. 13-15) describing prodrugs generally, is hereby incorporated.
As used herein C1-3alkyl as a group or part of a group defines straight or branched chain saturated hydrocarbon radicals having from 1 to 3 carbon atoms such as methyl, ethyl, propyl, 1-methylethyl and the like; C1-4alkyl as a group or part of a group defines straight or branched chain saturated hydrocarbon radicals having from 1 to 4 carbon atoms such as the group defined for C1-3alkyl and butyl and the like; C2-4alkyl as a group or part of a group defines straight or branched chain saturated hydrocarbon radicals having from 2 to 4 carbon atoms such as ethyl, propyl, 1-methylethyl, butyl and the like; C1-6alkyl as a group or part of a group defines straight or branched chain saturated hydrocarbon radicals having from 1 to 6 carbon atoms such as the groups defined for C1-4alkyl and pentyl, hexyl, 2-methylbutyl and the like; C1-9alkyl as a group or part of a group defines straight or branched chain saturated hydrocarbon radicals having from 1 to 9 carbon atoms such as the groups defined for C1-6alkyl and heptyl, octyl, nonyl, 2-methylhexyl, 2-methylhexyl and the like; C1-10alkyl as a group or part of a group defines straight or branched chain saturated hydrocarbon radicals having from 1 to 10 carbon atoms such as the groups defined for C1-9alkyl and decyl, 2-methylnonyl and the like. C3-7cycloalkyl is generic to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl; C2-5alkanediyl defines bivalent straight and branched chain saturated hydrocarbon radicals having from 2 to 5 carbon atoms such as, for example, 1,2-ethanediyl, 1,3-propanediyl, 1,4-butanediyl, 1,2-propanediyl, 2,3-butanediyl, 1,5-pentanediyl and the like, C2-5alkanediyl is substituted on C1-10alkyl as provided for in the definition of R2, it is meant to be substituted on one carbon atom thus forming a spiro moiety; C1-4alkanediyl defines bivalent straight and branched chain saturated hydrocarbon radicals having from 1 to 4 carbon atoms such as, for example, methylene, 1,2-ethanediyl, 1,3-propanediyl, 1,4-butanediyl and the like; C1-6alkanediyl is meant to include C1-4alkanediyl and the higher homologues thereof having from 5 to 6 carbon atoms such as, for example, 1,5-pentanediyl, 1,6-hexanediyl and the like; C1-10alkanediyl is meant to include C1-6alkanediyl and the higher homologues thereof having from 7 to 10 carbon atoms such as, for example, 1,7-heptanediyl, 1,8-octanediyl, 1,9-nonanediyl, 1,10-decanediyl and the like.
As used herein before, the term (xe2x95x90O) forms a carbonyl moiety when attached to a carbon atom, a sulfoxide moiety when attached to a sulfur atom and a sulfonyl moiety when two of said terms are attached to a sulfur atom. The term (xe2x95x90Nxe2x80x94OH) forms a hydroxylimine moiety when attached to a carbon atom.
The term halo is generic to fluoro, chloro, bromo and iodo. As used in the foregoing and hereinafter, polyhaloC1-6alkyl as a group or part of a group is defined as mono- or polyhalosubstituted C1-6alkyl, in particular methyl with one or more fluoro atoms, for example, difluoromethyl or trifluoromethyl. In case more than one halogen atoms are attached to an alkyl group within the definition of polyhaloC1-4alkyl, they may be the same or different.
When any variable (e.g. aryl, R2, R3, R4, R5a, R5b etc.) occurs more than one time in any constituent, each definition is independent.
It will be appreciated that some of the compounds of formula (I) and their prodsugs, N-oxides, addition salts, quaternary amines, metal complexes and stereochemically isomeric forms may contain one or more centers of chirality and exist as stereochemically isomeric forms.
The term xe2x80x9cstertochemically isomeric formsxe2x80x9d as used hereinbefore defines all the possible stereoisomeric forms which the compounds of formula (I), and their prodrugs, N-oxides, addition salts, quaternary amines, metal complexes or physiologically functional derivatives may possess. Unless otherwise mentioned or indicated, the chemical designation of compounds denotes the mixture of all possible stereo-chemically isomeric forms, said mixtures containing all diastereomers and enantiomers of the basic molecular structure as well as each of the individual isomeric forms of formula (I) and their prodrugs, N-oxides, salts, solvates or quaternary amines substantially free, i.e. associated with less than 10%, preferably less than 5%, in particular less than 2% and most preferably less than 1% of the other isomers. Stereochemically isomeric forms of the compounds of formula (I) are obviously intended to be embraced within the scope of this invention. As used hereinafter the terms R or S are well-known by the person skilled in the art
For some of the compounds of formula (I), their prodrugs, N-oxides, salts, solvates, quaternary amines, or metal complexes and the intermediates used in the preparation thereof, the absolute stereocherical configuration was not experimentally determined. In these cases the stereoisomeric form which was first isolated is designated as xe2x80x9cAxe2x80x9d and the second as xe2x80x9cBxe2x80x9d, without further reference to the actual stereochemical configuration. However, said xe2x80x9cAxe2x80x9d and xe2x80x9cBxe2x80x9d stereoisomeric forms can be unambiguously characterized by for instance their optical rotation in case xe2x80x9cAxe2x80x9d and xe2x80x9cBxe2x80x9d have an enantiomeric relationship. A person skilled in the art is able to determine the absolute configuration of such compounds using art-known methods such as, for example, X-ray diffraction. In case xe2x80x9cAxe2x80x9d and xe2x80x9cBxe2x80x9d are stereoisomeric mixtures, they can be further separated whereby the respective first fractions isolated are designated xe2x80x9cA1xe2x80x9d and xe2x80x9cB1xe2x80x9d and the second as xe2x80x9cA2xe2x80x9d and xe2x80x9cB2xe2x80x9d, without further reference to the actual stereochemical configuration.
For therapeutic use, salts of the compounds of formula (I) are those wherein the counterion is pharmaceutically acceptable. However, salts of acids and bases which are non-pharmaceutically acceptable may also find use, for example, in the preparation or purification of a pharmaceutically acceptable compound. All salts, whether pharmaceutically acceptable or not are included within the ambit of the present invention.
The pharmaceutically acceptable acid and base addition salts as mentioned hereinabove are meant to comprise the therapeutically active non-toxic acid and base addition salt forms which the compounds of formula (I) are able to form. The pharmaceutically acceptable acid addition salts can conveniently be obtained by treating the base form with such appropriate acid. Appropriate acids comprise, for example, inorganic acids such as hydrohalic acids, e.g. hydrochloric or hydrobromic acid, sulfuric, nitric, phosphoric and the like acids; or organic acids such as, for example, acetic, propanoic, hydroxyacetic, lactic, pyruvic, oxalic (i.e. ethanedioic), malonic, succinic (i.e. butane-dioic acid), maleic, fumaric, malic (i.e. hydroxybutanedioic acid), tararic, citric, methanesulfonic, ethanesulfonic, benzenesulfonic, p-toluenesulfonic, cyclamic, salicylic, p-aminosalicylic, pamoic and the like acids.
Conversely said salt forms can be converted by treatment with an appropriate base into the free base form.
The compounds of formula (I) containing an acidic proton may also be converted into their non-toxic metal or amine addition salt forms by treatment with appropriate organic and inorganic bases. Appropriate base salt forms comprise, for example, the ammonium salts, the alkali and earth alkaline metal salts, e.g. the lithium, sodium, potassium, magnesium, calcium salts and the like, salts with organic bases, e.g. the benzathine, N-methyl-D-glucamine, hydrabamine salts, and salts with amino acids such as, for example, arginine, lysine and the like.
The term addition salt as used hereinabove also comprises the solvates which the compounds of formula (I) as well as the salts thereof, are able to form. Such solvate are for example hydrates, alcoholates and the like.
The term xe2x80x9cquaternary aminexe2x80x9d as used hereinbefore defines the quaternary ammonium salts which the compounds of formula (I) are able to form by reaction between a basic nitrogen of a compound of formula (I) and an appropriate quaternizing agent, such as, for example, an optionally subs substituted alkylhalide, arylhalide or arylalkylhalide, e.g. methyliodide or benzyliodide. Other reactants with good leaving groups may also be used, such as alkyl trifluoromethanesulfonates, alkyl methanesulfonates, and alkyl p-toluenesulfonates. A quaternary amine has a positively charged nitrogen. Pharmaceutically acceptable counterions include chloro, bromo, iodo, trifluoroacetate and acetate. The counterion of choice can be introduced using ion exchange resins.
It will be appreciated that the compounds of formula (I) may have metal binding, chelating, complexating properties and therefore may exist as metal complexes or metal chelates. Such metalated derivatives of the compounds of formula (I) are intended to be included within the scope of the present invention.
Some of the compounds of formula (I) may also exist in their tautomeric form. Such forms although not explicitly indicated in the above formula are intended to be included within the scope of the present invention.
A special group of com pounds are those compounds of formula (I) wherein one or more of the following restrictions apply:
Q is a radical of formula (b-1), (b -3), (b-4), (b-5), (b -6), (b-7) or (b-8);
X2 is a direct bond, CH2 or C(xe2x95x90);
R2 is hydrogen, pyrrolidinyl, piperidinyl, homopiperidinyl, C3-7cycloalkyl substituted with NHR6, or C1-10alkyl substituted with NHR6 and optionally with a second, third or fourth substituent selected from amino, hydroxy, C3-7cycloalkyl, C2-5alkanediyl, piperidinyl, mono- or di(C1-6alkyl)amino, C1-6alkyloxycarbonylamino, aryl and aryloxy;
R3 is hydrogen, hydroxy, C1-6alkyl, C1-6alkyloxy or arylC1-6alkyl;
R6 is hydrogen, C1-4alkyl, formyl, C1-6alkylcarbonyl or C1-6alkyloxycarbonyl.
Also an interesting group of compounds are those compounds of formula (I) wherein one or more of the following restrictions apply:
xe2x80x94a1xe2x95x90a2xe2x80x94a3xe2x95x90a4xe2x80x94 is a radical of formula (a-1) or (a-2);
R1 is phenyl optionally substituted with halo, C1-6alkyl or C1-4alkyloxy; or pyridyl optionally substituted with 1 or more substituents selected from arylC1-6alkyloxy, C1-6-alkyloxyC1-4alkyl, aryl, mono- or di(C1-6alkyl)amino, C(xe2x95x90O)xe2x80x94NR5cR5d, halo or C1-6alkyl;
G is C1-4alkanediyl substituted with hydroxy, C1-6alkyloxy, HO(xe2x80x94CH2xe2x80x94CH2O)nxe2x80x94, C1-6alkyloxy(xe2x80x94CH2xe2x80x94CH2xe2x80x94O)nxe2x80x94 or arylC1-6alkyloxy(xe2x80x94CH2CH2xe2x80x94O)nxe2x80x94;
Q is a radical of formula (b-5) wherein v is 2, and Y1 is Nxe2x80x94R2;
X1 is NH or CH2;
R2 is hydrogen or C1-10alkyl substituted with NHR6 wherein R6 is hydrogen or C1-6alkyloxycarbonyl.
Particular compounds are those compounds of formula (I) wherein R2 is C1-10alkyl substituted with NH2.
Other particular compounds are those compounds of formula (I) wherein G is methylene or 1,2-ethanediyl, both substituted with hydroxy, C1-6alkyloxy, xe2x80x94HO(xe2x80x94CH2xe2x80x94CH2xe2x80x94O)nxe2x80x94, C1-6alkyloxy(xe2x80x94CH2xe2x80x94CH2xe2x80x94O)nxe2x80x94 or arylC1-6alkyloxy(xe2x80x94CH2xe2x80x94CH2xe2x80x94O)nxe2x80x94.
Also particular compounds are those compounds of formula (I) wherein R1 is pyridyl, preferably 2-pyridyl, substituted with one or 2 substituents selected from halo, hydroxy, amino, cyano, carboxy, C1-6alkyl, C1-6alkyloxy, C1-6alkylthio, C1-6alkyloxyC1-6alkyl, aryl, arylC1-6alkyl, arylC1-6alkyloxy, hydroxyC1-6alkyl, mono- or di(C1-6alkyl)amino, mono- or di(C1-6alkyl)aminoC1-6alkyl, polyhaloC1-6alkyl, C1-6alkylcarbonylamino, C1-6alkyl-SO2xe2x80x94NR5cxe2x80x94, aryl-SO2xe2x80x94NR5cxe2x80x94, C1-6alkyloxycarbonyl, xe2x80x94C(xe2x95x90O)xe2x80x94NR5cR5d, HO(xe2x80x94CH2xe2x80x94CH2xe2x80x94O)nxe2x80x94, halo(xe2x80x94CH2xe2x80x94CH2O)nxe2x80x94, C1-6alkyloxy(xe2x80x94CH2xe2x80x94CH2xe2x80x94O)nxe2x80x94, arylC1-6alkyloxy(xe2x80x94CH2xe2x80x94CH2xe2x80x94O)nxe2x80x94 and mono- or di(C1-6alkyl)amino(xe2x80x94CH2xe2x80x94CH2xe2x80x94O)nxe2x80x94, preferably selected from arylC1-6alkyloxy, C1-6alkyloxyC1-6alkyl, aryl, mono- or di(C1-6alkyl)amino, C(xe2x95x90O)xe2x80x94NR5aR5b, halo or C1-6alkyl.
Preferred compounds are those compounds of formula (I) wherein R1 is an optionally substituted 2-pyridyl moiety, in particular, a 2-pyridyl, a 6-substituted-2-pyridyl or a 3,6-disubstituted-2-pyridyl moiety.
Preferred compounds are
[(A),(S)]-N-[-1-(2-amino3-methylbutyl)-4-piperidinyl]-1-[(6-bromo-2-pyridinyl)-ethoxymethyl]-1H-benzimidazol-2-amine (compound 69);
[(A),(S)]-N-1-(2-aminopropyl)-4-piperidinyl]1-[ethoxy(6-methyl-2-pyridinyl)methyl]-1H-benzimidazol-2-amine (compound 75);
(xc2x1)-N-[1-(2-amino-3-methylbutyl)-4-piperidinyl]-1-[(2-methoxyethoxy)(6-methyl-2-pyridinyl)methyl]-1H-benzimidazol-2-amine (compound 86);
N-[1-(2-amino-3-methylbutyl)-4-piperidinyl]-6-chloro-1-[(2-methoxyethoxy)(6-methyl-2-pyridinyl)methyl]-4-methyl-1H-benzimidazol-2-amine trihydrochloride trihydrate (compound 88);
[(A),(R)]-N-[1-(2-amino-3-methylbutyl)-4-piperidinyl]-1-[ethoxy(6-methyl-2-pyridinyl)methyl]-1H-benzimidazol-2-amine monohydrate (compound 68);
(xc2x1)-N-[1-(2-aminopropyl)-4-piperidinyl]-1[-ethoxy(6-methyl-2-pyridinyl)methyl]-1H-benzimidazol-2-amine monohydrate (compound 12);
[(A)(S)]-N-[1-(2-amino-3-methylbutyl)-4-piperidinyl]-1-[ethoxy(6-methyl-2-pyridinyl)methyl]-1H-benzimidazol-2-amine monohydrate (compound 67);
(xc2x1)-N-[1-(2-amino-3-methylbutyl)-4-piperidinyl]-1-[ethoxy(6-methyl-2-pyridinyl)-methyl]-1H-benzimidazol-2-amine (compound 83);
[(A),(R)]-N-[1-(2-aminopropyl)-4-piperidinyl]-1-[ethoxy(6-methyl-]2-pyridinyl)methyl]-1H-benzimidazol-2-amine monohydrate (compound 74);
(xc2x1)-N-[1-(2-aminopropyl)-4-piperidinyl]-1-[(6-bromo-2-pyridinyl)ethoxymethyl]-2-benzimidazol-2-amine (compound 9);
(xc2x1)-N-[1-[-(2-aminoethyl)-4-piperidinyl]-1-[(2-ethoxyethoxy)(6-methyl-2-pyridinyl)-methyl]-1H-benzimidazol-2-amine (compound 64);
[(B),(S)]N-[1-(2-aminopropyl)-4-piperidinyl]-1-[ethoxy(6-methyl-2-pyridinyl)methyl]-1H-benzimidazol-2-amine monohydrate (compound 76);
(xc2x1)-N-[1(2-amino-3-methylbutyl)-4-piperidinyl]-3-[(2-methoxyethoxy)(6-methyl-2-pyridinyl)methyl]-7-methyl-3H-imidazo[4,5-b]pyridin-2-amine (compound 89);
(xc2x1)-N-[1-(2-amino-3-methylbutyl)-4-piperidinyl]-1-[(2-ethoxyethoxy)(6-phenyl-2-pyridinyl)methyl]-1H-benzimidazol-2-amine (compound 85);
(xc2x1)-N-[1-(2-aminoethyl)-4-piperidinyl]-1-[(2-methoxyethoxy)(6-methyl-2-pyridinyl)-methyl]-1H-benzimidazol-2-amine (compound 82);
the prodrugs, N-oxides, addition salts, quaternary amines, metal complexes and stereochemically isomeric forms thereof.
Most preferred are
(xc2x1)-N-[1-(2-amino-3-methylbutyl)-4-piperidinyl]-1-[(6-bromo-2-pyridinyl)ethoxy-methyl]-4-methyl-1H-benzimidazol-2-amine monohydrate (compound 87);
[(A),(R)]-N-[1-(2-amino-3-methylbutyl)-4-piperidinyl]-1-[(6-bromo-2-pyridinyl)-ethoxymethyl]-1H-benzimidazol-2-amine (compound 70);
(xc2x1)-N-[1-(2-amino-3-methylbutyl)-4-piperidinyl]-1-[(6-bromo-2-pyridinyl)ethoxy-methyl]-1H-benzimidazol-2-amine (compound 10);
the prodrugs, N-oxides, addition salts, quaternary amines, metal complexes and stereochemically isomeric forms thereof.
In general, compounds of formula (I) can be prepared by reacting an intermediate of formula (II-a) or (I-b), wherein P represents a protecting group, such as, for example C1-4alkyloxycarbonyl, or those protecting groups mentioned in Chapter 7 of xe2x80x98Protective Groups in Organic Synthesisxe2x80x99 by T Greene and P. Wuyts (John Wiley and Sons Inc., 1991) with an intermediate of formula (III), wherein W1 is a suitable leaving group, such as a halo atom, e.g. chloro, bromo, in the presence of a suitable base, such as, e.g. sodium hydride. Said reaction can be performed in a reaction-inert solvent, such as N,N-dimethylformamide. 
Compounds of formula (I) wherein, in the definition of Q, R2 or at least one R6 substituent is hydrogen, said Q being represented by H-Q1, and said compounds being represented by formula (I-a), can be prepared by deprotecting an intermediate of formula (IV) wherein P represents a protecting group, for example C1-4alkyloxycarbonyl, benzyl, or those protecting groups mentioned in Chapter 7 of xe2x80x98Protective Groups in Organic Synthesisxe2x80x99 by T Greene and P. Wuyts (John Wiley and 
When P represents, for example, C1-4alkyloxycarbonyl, said deprotection reaction can be performed by, for example, acidic hydrolysis in the presence of a suitable acid, such as hydrobromic, hydrochloric, sulfuric, acetic, or trifluoroacetic acid or a mixture of said acids, or by alkaline hydrolysis in the presence of a suitable base, such as, for example potassium hydroxide, in a suitable solvent such as water, alcohol, a mixture of water-alcohol, nethylene chloride. Suitable alcohols are methanol, ethanol, 2-propanol, 1-butanol and the like. In order to enhance the rate of the reaction, it is advantageous to heat the reaction mixture, in particular up to the reflux temperature. Alternatively, when P represents, for example, benzyl, the deprotection reaction can be performed by catalytic hydrogenation in the presence of hydrogen and an appropriate catalyst in a reaction-inert solvent. A suitable catalyst in the above reaction is, for example, platinum-on-charcoal, palladium-on-charcoal, and the like. An appropriate reaction-inert solvent for said reaction is, for example, an alcohol, e.g. methanol, ethanol, 2-propanol and the like, an ester, e.g. ethylacetate and the like, an acid, e.g. acetic acid and the like.
The catalytic hydrogenation reaction described above can also be used to prepare a compound of formula (I-a) by deprotecting and reducing an intermediate of formula (IV) wherein Q1 comprises an unsaturated bond, said Q1 being represented by Q1a(CHxe2x95x90CH), and said intermediate being represented by formula (IV-a). 
Compounds of formula (I) wherein, in the definition of Q, both R6 substituents are hydrogen or R2 and R4 are both hydrogen, said Q being represented by H2Nxe2x80x94Q2, and said compounds being represented by formula (I-a-1), can also be prepared by deprotecting an intermediate of formula (V). 
Said deprotection reaction can be performed in the presence of a suitable base such as, for example hydrazine, or in the presence of a suitable acid, such as hydrochloric acid and the like, in a suitable solvent, such as an alcohol, acetic acid and the like.
Compounds of formula (I-a-1) can also be prepared by deprotecting an intermediate of formula (VI) according to the procedure described for the preparation of compounds of formula (I-a). 
Compounds of formula (I-a) or (I-a-1), wherein Q1, or Q2, comprise a hydroxy substituent, said Q1 or Q2 being represented by Q1xe2x80x2(OH) or Q2xe2x80x2(OH), and said compounds being represented by formula (I-a-2) or (I-a1-a-1-1), can be prepared by deprotecting an intermediate of formula (VII) or (VIII) as described hereinabove for the preparation of compounds of formula (I-a). 
Compounds of formula (I) wherein, in the definition of Q, both R6 substituents are hydrogen or R2 and R4 are both hydrogen, and the carbon adjacent to the nitrogen carrying the R6, or R2 and R4 substituents contains at least one hydrogen, said Q being represented by H2Nxe2x80x94Q3H, and said compounds being represented by formula (I-a-1-2) can also be obtained by reductive animation of intermediates of formula (IX) in the presence of a suitable animation reagent, such as, for example, ammonia, hydroxylamine, or benzylamine, and in the presence of a suitable reducing agent, e.g. hydrogen, and an appropriate catalyst. An appropriate catalyst in the above reaction is, for example, platinum-on-charcoal, palladium-on-charcoal, rhodiumon-Al2O3, and the like, optionally in the presence of a catalyst poison, such as a thiophene solution. A suitable reaction-inert solvent for the above reaction is, for example, an alcohol, e.g. methanol, ethanol, 2-propanol and the like. 
Compounds of formula (I), wherein Q comprises a xe2x80x94CH2NH2 moiety, said Q being represented by H2Nxe2x80x94CH2xe2x80x94Q4, and said compounds being represented by formula (I-a-1-3) can be prepared by reducing an intermediate of formula (X). 
Said reduction can be performed with a suitable reducing agent, such as lithium aluminium hydride or hydrogen, optionally in the presence of a suitable catalyst, such as Raney Nickel. A suitable solvent for the above reaction is, for example, tetrahydrofuran, or a solution of ammonia in an alcohol. Suitable alcohols are methanol, ethanol, 2-propanol and the like. Said reduction reaction performed in a solution of ammonia in an alcohol can also be used to prepare compounds of formula (I-a-1-3), wherein R1 is substituted with C1-6alkyloxyC1-6alkyl, said R1 being represented by R1xe2x80x2xe2x80x94C1-6alkyloxyC1-6alkyl, and said compounds being represented by formula (I-a-1-3-1) starting from an intermediate of formula (X-a). 
Compounds of formula (I), wherein Q comprises a xe2x80x94CH2xe2x80x94CHOHxe2x80x94CH2xe2x80x94NH2 moiety, said Q being represented by H2Nxe2x80x94H2xe2x80x94CHOHxe2x80x94CH2xe2x80x94Q4, and said compounds being represented by formula (I-a-1-3-2), can be prepared by reacting an intermediate of formula (XI) with ammonia in the presence of a suitable reaction-inert solvent, such as an alcohol, e.g. methanol. 
Compounds of formula (I), wherein, in the definition of Q, R2 or one R6 substituent is formyl, said Q being represented by Hxe2x80x94C(xe2x95x90O)xe2x80x94Q1, and said compounds being represented by formula (I-b), can be prepared by reacting an intermediate of formula (XII) with formic acid, formamide and ammonia. 
Compounds of formula (I), wherein, in the definition of Q, R2 is other than hydrogen, said R2 being represented by R2a, R4 is hydrogen, and the carbon atom adjacent to the nitrogen atom carrying the R2 and R4 substituents, carries also at least one hydrogen atom, said Q being represented by R2axe2x80x94NHxe2x80x94HQ5, and said compounds being represented by formula (I-c), can be prepared by reductive amination of an intermediate of formula (XIII) with an intermediate of formula (XIV) in the presence of a suitable reducing agent, such as hydrogen, and a suitable catalyst, such as palladium-on-charcoal, platinum-on-charcoal, and the like. A suitable reaction-inert solvent for the above reaction is, for example, an alcohol, e.g. methanol, ethanol, 2-propanol and the like. 
Compounds of formula (I-c), wherein R2a represents C1-10alkyl substituted with N(R6)2 and with hydroxy, and the carbon atom carrying the hydroxy, carries also two hydrogen atoms, said R2a being represented by [(C1-9alkyl)CH2OH]xe2x80x94N(R6)2, and said compounds being represented by formula (I-c-1), can be prepared by reducing an intermediate of formula (XV) in the presence of a suitable reducing agent, such as lithium aluminium hydride, in a suitable reaction-inert solvent, such as tetrahydrofuran. 
Compounds of formula (I) wherein, in the definition of Q, R2 or one R6 substituent is hydrogen, said Q being represented by H-Q1, and wherein R1 is aryl or a monocyclic heterocycle substituted with 1 or more substituents selected from hydroxy, hydroxyC1-6alkyl, or HO(xe2x80x94CH2CH2xe2x80x94O)nxe2x80x94, said substituents being represented by formula Axe2x80x94OH, said R1 being represented by R1axe2x80x94(Axe2x80x94O)w, with w being the amount of substituents on R1a ranging from 1 to 4, and said compounds being represented by formula (I-d), can be prepared by deprotecting an intermediate of formula (XVI) with a suitable acid, such as hydrochloric acid and the like, optionally in the presence of a suitable solvent, such as an alcohol. Suitable alcohols are methanol, ethanol, 2-propanol and the like.
Alternatively, one protecting group may also protect more than one substituent of R1a, said protecting group being represented by P1, as represented by formula (XVI-a). The two ways of protecting the substituents of R1a, i.e. with a separate, as in formula (XVI), or a combined, as in formula (XVI-a), protecting group, may also be combined in the same intermediate, as represented by formula (XVI-b). 
Compounds of formula (I), wherein Q is a radical of formula (b-2), said compounds being represented by formula (I-e), can be prepared by reacting an intermediate of formula (XVII) with an intermediate of formula (XVIII) in the presence of sodium cyanide and a suitable reaction-inert solvent, such as an alcohol, e.g. methanol and the like. 
Compounds of formula (I), wherein in the definition of Q, X2 is C2-4alkyl-NR4, said Q being represented by Q6Nxe2x80x94CH2xe2x80x94C1-3alkyl-NR4, and said compounds being represented by formula (I-p), can be prepared by reacting an intermediate of formula (XIX) with an intermediate of formula (XX) in the presence of isopropyl titanate (IV) and a suitable reducing agent, such as NaBH3CN, and in the presence of a suitable reaction-inert solvent, such as methylene chloride and an alcohol, e.g. ethanol. 
Compounds of formula (I-p), wherein R2 is C1-6alkylcarbonyl, and Q is a radical of formula (b-6), wherein Y1 is NR2, said compounds being represented by formula (I-p-1), can be prepared by reacting an intermediate of formula (XIX) with an intermediate of formula (XX-a according to the procedure described for the preparation of a compound of formula (I-p). 
Compounds of formula (I), wherein G is substituted with hydroxy or HO(xe2x80x94CH2CH2O)nxe2x80x94, said Q being represented by G1xe2x80x94OH, and said compounds being represented by formula (I-q), may be prepared by deprotecting an intermediate of formula (XXI), wherein P represents a suitable protecting group, for example, benzyl. Said deprotection reaction can be performed by catalytic hydrogenation in the presence of hydrogen and an apropriate catalyst in a reaction-inert solvent. A suitable catalyst in the above reaction is, for example, platinum-on-charcoal, palladium-on-charcoal, and the like. An apropriate reaction-inert solvent for said reaction is, for example, an alcohol, e.g. methanol, ethanol, 2-propanol and the like, an ester, e.g. ethylacetate and the like, an acid, e.g. acetic acid and the like. 
Compounds of formula (I), wherein G is substituted with hydroxy and the carbon atom carrying the hydroxy substituent carries also at least one hydrogen, said G being represented by Hxe2x80x94G2xe2x80x94OH, and said compounds being represented by formula (I-q-1), can also be prepared by reducing an intermediate of formula (XXI). 
Said reduction reaction can be performed in the presence of a suitable reducing agent, such as, for example sodium borohydride, in a reaction-inert solvent, such as an alcohol or tetrahydrofuran or a mixture thereof. Suitable alcohols are methanol, ethanol, 2-propanol and the like.
Compounds of formula (I) may be converted into each other following art-known functional group transformation reactions, comprising those described hereinafter.
The compounds of formula (I) may be converted to the corresponding N-oxide forms following art-known procedures for converting a trivalent nitrogen into its N-oxide form. Said N-oxidation reaction may generally be carried out by reacting the starting material of formula (I) with an appropriate organic or inorganic peroxide. Appropriate inorganic peroxides comprise, for example, hydrogen peroxide, alkali metal or earth alkaline metal peroxides, e.g. sodium peroxide, potassium peroxide; appropriate organic peroxides may comprise peroxy acids such as, for example, benzenecarboperoxoic acid or halo substituted benzenecarboperoxoic acid, e.g. 3-chlorobenzenecarboperoxoic acid, peroxoalkanoic acids, e.g. peroxoacetic acid, alkylhydroperoxides, e.g. t.butyl hydro-peroxide. Suitable solvents are, for example, water, lower alcohols, e.g. ethanol and the like, hydrocarbons, e.g. toluene, ketones, e.g. 2-butanone, halogenated hydrocarbons, e.g. dichloromethane, and mixtures of such solvents.
Compounds of formula (I), wherein R1 is monocyclic heterocycle substituted with C1-6alkyloxycarbonyl, said R1 being represented by R1xe2x80x2xe2x80x94C(xe2x95x90O)OC1-6alkyl, and said compounds being represented by formula (I-f), can be prepared by esterification of a compound of formula (I-g) in the presence of a suitable alcohol, e.g. methanol, ethanol, propanol, butanol, pentanol, hexanol and the like, and in the presence of a suitable acid, such as hydrochloric acid and the like. 
Compounds of formula (I-a) may be converted into compounds of formula (I) wherein, in the definition of Q, R2 or at least one R6 substituent is other than hydrogen, said R2 or R6 being represented by Z1, said Q being represented by Z1xe2x80x94Q1, and said compounds being represented by formula (I-h), by reaction with a reagent of formula (XXIII), wherein W2 is a suitable leaving group, such as a halo atom, e.g. bromo, or 4-methylbenzenesulphonate, in the presence of a suitable base, such as, for example disodium carbonate, dipotassium carbonate, sodium hydroxide and the like, in a reaction-inert solvent, e.g. 3-methyl-2-butanone, acetonitrile, N,N-dimethylformamide. 
Compounds of formula (I-h), wherein, in the definition of Z1, R2 is CH2xe2x80x94C1-9alkyl substituted with N(R6)2, said compounds being represented by formula (I-h-1), can also be prepared by reacting a compound of formula (I-a) wherein, in the definition of Hxe2x80x94Q1, R2 is hydrogen, said Hxe2x80x94Q1, being represented by Hxe2x80x94Q1b, and said compounds being represented by formula (I-a-3), with an intermediate of formula (XXIV), in the presence of a suitable reducing agent, such as sodium cyanoborohydride, in a suitable reaction-inert solvent, such as an alcohol. 
Compounds of formula (I-h), wherein Z1 comprises formyl, C1-6alkylcarbonyl, Hetcarbonyl or C1-6akyloxycarbonyl, said Z1 being represented by Z1a, and said compounds being represented by formula (I-h-2), can be converted into compounds of formula (I-a), by acidic hydrolysis in the presence of a suitable acid, such as hydrobromic, hydrochloric, sulfuric, acetic, or trifluoroacetic acid or a mixture of said acids, or by alkaline hydrolysis in the presence of a suitable base, such as, for example potassium hydroxide, in a suitable solvent such as water, alcohol, a mixture of water-alcohol, methylene chloride. Suitable alcohols are methanol, ethanol, 2-propanol, 1-butanol, sec. butanol and the like. In order to enhance the rate of the reaction, it is advantageous to work at elevated temperatures. 
Compounds of formula (I-b) can be prepared by reacting a compound of formula (I-a) with formic acid 
Compounds of formula (I) wherein R1 is monocyclic heterocycle or aryl substituted with hydroxy, said R1 being represented by HOxe2x80x94R1, and said compounds being represented by formula (I-i), can be prepared by deprotecting a compound of formula (I-j), wherein R1 is monocyclic heterocycle or aryl substituted with C1-6alkyloxy or arylC1-6alkyloxy, said C1-6alkyl or arylC1-6alkyl being represented by Z2, and said R1 being represented by Z2xe2x80x94Oxe2x80x94R1xe2x80x2. Said deprotection can be performed in a raction-inert solvent, such as, for example methylene chloride, in the presence of a suitable deprotecting agent, e.g. tribromoborane. 
Compounds of formula (I) wherein R1 is monocyclic heterocycle substituted with halo(xe2x80x94CH2xe2x80x94CH2xe2x80x94O)n, said compounds being represented by formula (I-k), can be converted into compounds of formula (I-1-1) or (I-1-2) by reaction with an appropriate amine of formula (XXV) or (XXVI) in a suitable reaction-inert solvent, e.g. tetrahydrofuran. 
Compounds of formula (I) wherein R1 is monocyclic heterocycle or aryl substituted with halo, said compounds being represented by formula (I-m) can be converted into. compounds of formula (I) by reaction with 1-butanethiol in the presence of palladium-on-charcoal and CaO in a suitable reaction-inert solvent, such as tetrahydrofuran. 
Compounds of formula (I) wherein a hydrogen atom in the radicals of formula (a-1), (a-2), (a-3), (a4) or (a-5) is replaced by nitro, said compounds being represented by formula (I-n) may be reduced to a compound of formula (I-o) in the presence of a suitable reducing agent, such as hydrogen, optionally in the presence of a suitable catalyst, such as platinum-on-charcoal, and optionally in the presence of a suitable catalyst poison, e.g. a thiophene solution. The reaction may be performed in a suitable reaction-inert solvent, such as an alcohol. 
In the following paragraphs, there are described several methods of preparing the intermediates in the foregoing preparations. A number of intermediates and starting materials are commercially available or are known compounds which may be prepared according to conventional reaction procedures generally known in the art or analogous to the procedures described in EP-A-0005318, EP-A-0099139, EP-A-0151824, EP-A-0151826, EP-A-0232937, EP-A-0295742, EP-A-0297661, EP-A-0539420, EP-A-0539421, U.S. Pat. No. 4,634,704, U.S. Pat. No. 4,695,569.
In the foregoing and the following preparations, the reaction mixture is worked up following art-known methods and the reaction product is isolated and, if necessary, further purified.
Intermediates of formula (III) can be prepared by reacting an intermediate of formula (XXVII) with a suitable leaving group, i.e. W1, introducing agent, e.g. 1-halo-2,5-pyrrolidinedione in the presence of dibenzoyl peroxide, in a reaction-inert solvent, e.g. tetrachloromethane. 
Intermediates of formula (XXVII), wherein R1 is monocyclic heterocycle or aryl substituted with chloro, said R1 being represented by Clxe2x80x94R1xe2x80x2 and said intermediates being represented by formula (XXVII-a) can be prepared by reacting an intermediate of formula (XXVIII), wherein (Oxe2x95x90)R1bH is defined as a carbonyl derivative of R1xe2x80x2 wherein one carbon or nitrogen, adjacent to the carbonyl, carries at least one hydrogen, with phosphorus oxychloride. Intermediates of formula (XXVIII) may also react as their enol tautomeric forms. 
Intermediates of formula (III) wherein W1 is chloro, which is attached to a carbon atom carrying at least one hydrogen, said G being represented by G3H, and said intermediates being represented by formula (III-a) can also be prepared by reacting an intermediate of formula (XXIX) with thionylchloride in a reaction-inert solvent, e.g. methylenechloride. 
Intermediates of formula can be prepared by reducing an intermediate of formula (XXXI) in a reaction-inert solvent, e.g. an alcohol, in the presence of a suitable reducing agent, e.g. sodium borohydride. 
Alternatively, intermediates of formula (XXIX) can also be prepared by deprotecting an intermediate of formula (XXXI), wherein P is a suitable protecting group, e.g. C1-4alkylcarbonyl, in a reaction-inert solvent, such as an alcohol, in the presence of a suitable base, e.g. sodium hydroxide. 
Intermediates of formula (XXX), wherein G3(xe2x95x90O) is CH(xe2x95x90O), said intermediates being represented by formula (XXX-a), can be prepared by reacting an intermediate of formula (XXXII), wherein W3 is a suitable leaving group, such as a halo atom, e.g. bromo, with N,N-dimethylformamide in the presence of butyllithium in a reaction-inert solvent, e.g. tetrahydrofuran, diethylether or a mixture thereof. 
Intermediates of formula (IV) can be prepared by reacting an intermediate of formula (XXXIII-a) or (XXXIII-b), wherein P reresents a suitable protecting group, such as, for example, C1-4alkyloxycarbonyl, with an intermediate of formula (III) according to the reaction described for the general preparation of compounds of formula (I). 
Intermediates of formula (IV) can also be prepared by reacting an intermediate of formula (XXXIII-a) with an intermediate of formula (XXXIV) that has reacted with methanesulfonyl chloride, in the presence of a suitable base, such as sodium hydride, and in the presence of a suitable reaction-inert solvent, e.g. N,N-dimethylformamide. 
Intermediates of formula (IV) can also be prepared by a cyclization reaction of an intermediate of formula (XXXV) in a reaction-inert solvent, e.g. an alcohol or N,N-dimethylformamide, in the presence of mercury oxide and sulphur. 
Intermediates of formula (IV) wherein Q1 comprises an unsaturated bond, said Q1 being represented by Q1a(CHxe2x95x90CH), and said intermediates by formula (IV-a), can be prepared by reacting an intermediate of formula (XXXVI) with an intermediate of formula (III) in the presence of a suitable base, such as dipotassium carbonate. 
Intermediates of formula (IV) wherein, in the definition of Q1, the X1 or X2 moieties in the radicals of formula (b-1) to (b-8) represent NH, said Q1 being represented by Q1cxe2x80x94NH, and said intermediates by formula (IV-b), may also be prepared by reacting an intermediate of formula (XXXVII) with an intermediate of formula (XXXIII). 
Intermediates of formula (IV) wherein R1 is monocyclic heterocycle substituted with amino or mono or di(C1-6alkyl)amino, said R1 being represented by R5aR5bNxe2x80x94R1xe2x80x2, wherein R5a and R5b are defined as described above, and said intermediates being represented by formula (IV-c), can be prepared by reacting an intermediate of formula (XXXIX) with an appropriate amine, represented by formula (XL), in the presence of an appropriate catalyst, e.g. palladium, and (R)-(+)-2,2xe2x80x2-bis(diphenyt-phosphino)-1,1xe2x80x2-binaphtyl, in a suitable reaction-inert solvent, e.g. tetrahydrofuran. 
Intermediates of formula (IV) wherein R1 is monocyclic heterocycle substituted with C(xe2x95x90O)xe2x80x94NR5aR5b, wherein R5a and R5b are defined as described above, said R1 being represented by R5aR5bNxe2x80x94C(xe2x95x90O)xe2x80x94R1xe2x80x2, and said intermediates being represented by formula (IV-d), can be prepared by reacting an intermediate of formula (XXXIX) with an appropriate amine, represented by formula (XL), under an atmosphere of carbon monoxide, in the presence of a suitable catalyst, e.g. palladium (II) acetate, and 1,3-bis(diphenylphosphino)propane, in a suitable reaction-inert solvent, e.g. tetaydrofuran. 
Intermediates of formula (IV) wherein P-Q1 comprises C1-10alkyl or C3-7cycloalkyl substituted with NR6xe2x80x94P, said C1-10alkyl or C3-7cycloalkyl being represented by Z3, said Pxe2x80x94Q1 being represented by Pxe2x80x94NR6xe2x80x94Z3Q1b, and said intermediates being represented by formula (IV-e), can be prepared by reacting a compound of formula (I-a3) with an intermediate of formula (XLI), wherein W4 represents a suitable leaving group, such as p-toluenesulphonate. Said reaction can be performed in a reaction-inert solvent, e.g. acetonitrile, in the presence of a suitable base, e.g. dipotassium carbonate. 
Intermediates of formula (IV-e), wherein R6 is hydroxyC1-6alkyl, said intermediates being represented by formula (V-e-1), can be prepared by reacting an intermediate of formula (XLII) with an intermediate of formula (XLIII) in the presence of a suitable base, e.g. dipotassium carbonate, and a suitable solvent, e.g. acetonitrile. 
Intermediates of formula (XXXIII-a) or XXXIII-b) can be prepared by protecting an intermediate of formula (XLIV) with a suitable protecting group, such as, for example, C1-4alkyloxycarbonyl, in a reaction-inert solvent, such as methylene chloride or an alcohol, e.g. methanol, ethanol, 2-propanol and the like, in the presence of a suitable reagent, e.g. di C1-4alkyl dicarbonate and optionally in the presence of a suitable base, e.g. sodium acetate. 
Alternatively, intermediates of formula (XXXIII-a) or (XXXIII-b) can be converted into an intermediante of formula (XLIV) by reaction with a suitable acid, such as hydrochloric acid or hydrobromic acid and the like or mixtures thereof, in the presence of a suitable solvent, e.g. water.
Intermediates of formula (XXXIII-a) or (XXXIII-b), wherein in the definition of Q1, the X1 or X2 moieties in the radicals of formula (b-1) to (b-8) represent NH, said Q1 being represented by Q1cxe2x80x94NH, and said intermediates by formula (XXXXIII-a-1) or (XXXXIII-a-1), can be prepared by reacting an intermediate of formula (XLV-a) or (XLV-b), wherein W5 represents a suitable leaving group, such as for example a halo atom, e.g. chloro, with an intermediate of formula (XLVI). 
Intermediates of formula (XLV-a) or (XLV-b) can be prepared by reacting an intermediate of formula (XLVII-a) or (XLVI-b) with H2P(xe2x95x90O)(W5)3 in the presence of a suitable acid, e.g. hydrochloric acid. 
Intermediates of formula (XLVII-a) or (XLVII-b) can be prepared by reacting an intermediate of formula (XLVIII-a) or (XLVIII-b) with an intermediate of formula (IL). 
Intermediates of formula (XXXIII-a) can also be prepared by reacting an intermediate of formula (XLVIII-a) with Pxe2x80x94Q1xe2x80x94C(xe2x95x90NH)xe2x80x94Oxe2x80x94CH2xe2x80x94CH3 in a reaction-inert solvent, such as an alcohol. 
Intermediates of formula (XXXV) can be prepared by reacting an intermediate of formula (L) with an intermediate of formula Pxe2x80x94Q1xe2x95x90Cxe2x95x90S, which is synthesized according to the procedures described in EP 0005318, in a reaction-inert solvent, such as an alcohol, e.g. ethanol. To increase the reaction rate, the reaction may be performed at elevated temperatures. 
Intermediates of formula (L) can be obtained by reducing an intermediate of formula (LI) in a reaction-inert solvent, e.g. an alcohol, in the presence of a suitable reducing agent, e.g. hydrogen, and an appropriate catalyst, e.g. Raney Nickel. 
Intermediates of formula (LI) can be prepared by reacting an intermediate of formula (LII) with an intermediate of formula (LIII), in which W6 represents a suitable leaving group, such as a halo atom, e.g. chloro. This reaction may be performed in a reaction-inert solvent, e.g. acetonitrile, in the presence of a suitable base, e.g. dipotassium carbonate. 
Intermediates of formula (LII) can be prepared by reacting an intermediate of formula (LIV) with a suitable acid, such as hydrochloric acid, in the presence of a suitable solvent, e.g. an alcohol, e.g. ethanol. 
Intermediates of formula (LIV) can be prepared by reacting an intermediate of formula (III) with NaN[C(xe2x95x90O)H]2. 
Intermediates of formula (LI) can also be prepared by reacting an intermediate of formula (LII) with an intermediate of formula (LV) (J. Org. Chem., 25, p 1138, 1960) in a reaction-inert solvent, e.g. N,N-dimethylformamide, in the presence of an appropriate base, e.g. sodium hydride. 
Intermediates of formula (XXXVI) can be prepared by dehydrating an intermediate of formula (LVI) with a suitable acid, such as sulfuric acid. 
Intermediates of formula (LVI) wherein, in the definition of Q1a, the X1 or X2 moieties are CH2, said Q1a being represented by Q1axe2x80x2, and said intermediates being represented by formula (LVI-a), can be prepared by reacting a carbonyl moiety of formula (LVII) with an intermediate of formula (LVIII) in the presence of N,N-diisopropylamine and butyl lithium, in a suitable reaction-inert solvent, e.g. tetrahydrofuran. 
Intermediates of formula (IV), wherein G is C1-10alkanediyl substituted with C1-6alkyloxy, arylC1-6alkyloxy, HO(xe2x80x94CH2CH2O)nxe2x80x94, C1-6alkyloxy(xe2x80x94CH2CH2O)nxe2x80x94, or arylC1-6alkyloxy(xe2x80x94CH2CH2O)nxe2x80x94, said group of substituents being represented by Oxe2x80x94Z4, said G being represented by Z4xe2x80x94Oxe2x80x94G1, and said intermediates being represented by formula (IV-f), can be prepared by reacting an intermediate of formula (XXXIII-a), with an intermediate of formula (LIX), optionally in the presence of a suitable acid, such as p-toluenesulfonic acid and the like, and optionally in the presence of a suitable solvent, such as N,N-dimethylacetamide. To increase the reaction rate, the reaction may be carried out at elevated temperatures. 
Intermediates of formula (LIX) can be prepared by reacting an intermediate of formula (LX) with a reagent of formula (LXI) or (LXII) in a reaction-inert solvent, such as an alcohol, or toluene, in the presence of an acid, e.g. 4-methylbenzenesulphonic acid. 
Intermediates of formula (LX) can be prepared by oxidizing an intermediate of formula (LXIII) with a suitable oxidizing agent, e.g. MnO2, in a reaction-inert solvent, such as methylene chloride. 
Intermediates of formula (IV-f) can also be prepared by reacting an intermediate of formula (IV) wherein G is C1-10alkanediyl substituted with hydroxy, said G being presented by G1xe2x80x94OH, and said intermediates being represented by formula (IV-g), with an intermediate of formula (LXIV), wherein W7 is a suitable leaving group, such as a halo atom, e.g. iodo, in the presence of a suitable base, e.g. sodium hydride, in a reaction-inert solvent, e.g. tetrahydrofuran. 
Intermediates of formula (IV-g), wherein the carbon atom of G1 carrying the hydroxy, also carries a hydrogen atom, said G1xe2x80x94OH being represented by Hxe2x80x94G2xe2x80x94OH, and said intermediates being represented by formula (IV-g-1), can be prepared by reducing an intermediate of formula (LXV) in the presence of a suitable reducing agent, e.g. sodium borohydride, in a reaction-inert solvent, such as an alcohol, tetrahydrofuran or a mixture thereof. Intermediates of formula (LXV) can also first be deprotected, e.g. in the presence of a suitable acid, such as hydrochloric acid and the like, resulting in intermediates of formula (LXVI), followed by a reduction, resulting in a compound of formula (I-q-1) wherein Q represents Hxe2x80x94Q1, said compounds being represented by formula (I-q1-1). 
Intermediates of formula (IV), wherein G is ethyl substituted with hydroxy, said intermediates being represented by formula (IV-g-2) can also be prepared by reacting an intermediate of formula (XXXIII-a) with an intermediate of formula (LXVII) in the presence of a suitable base, such as sodium hydride, in a reaction-inert solvent, such as N,N-dimethylformamide. 
A subgroup of intermediates of formula (IV-g-2), represented by formula (IV-g-2-1), can also be prepared by reacting an intermediate of formula (LXVIII) with an intermediate of formula (LXIX) in the presence of 1,3-dicyclohexylcarbodiimide, in a reaction-inert solvent, e.g. toluene. 
Intermediates of formula (LXV) can be prepared by reacting an intermediate of formula (XXXIII-a) with an intermediate of formula (LXX), wherein W8 is a suitable leaving group, such as a halo atom, e.g. bromo, in the presence of a suitable base, e.g. sodium hydride, in a reaction-inert solvent, e.g. N,N-dimethylformamide. 
Intermediates of formula (V) can be prepared by reacting an intermediate of formula (LXXI) with 1H-isoindole-1,3 (2H)-dione in the presence of triphenylphosphine and diethyl azodicarboxylate. 
Intermediates of formula (V) may also be prepared by reacting an intermediate of formula (LXXII) with 1H-isoindole-1,3 (2H)-dione in the presence of a suitable base, such as sodium hydride, and a suitable solvent, such as N,N-dimethylformamide. 
Intermediates of formula (LXXII) can be prepared by reacting an intermediate of formula (LXXI) with an intermediate of formula (LXXII), wherein W9 represents a suitable leaving group, such as a halo atom, e.g. chloro, in the presence of a suitable base, such as N,N-diethylethanamine, and a suitable solvent, such as methylene chloride. 
Intermediates of formula (V), wherein in the definition of Q2, R2 is C1-10alkyl, said Q2 being represented by C110alkyl-Q1b, and said intermediates by formula (V-a), can be prepared by reacting a compound of formula (I-a-3) with an intermediate of formula (LXXIV), wherein W10 is a suitable leaving group, such as a halo atom, e.g. chloro, in the presence of a suitable base, such as dipotassium carbonate, and a suitable solvent, such as acetonitrile. 
Intermediates of formula (LXXI) wherein, in the definition of Q2, the carbon atom carrying the hydroxy, also carries two hydrogen atoms, said HOxe2x80x94Q2 being represented by HOxe2x80x94CH2Q2xe2x80x2, and said intermediates being represented by formula (LXXI)-a), can be prepared by reducing an intermediate of formula (LXXV) in the presence of a suitable reducing agent, such as lithium aluminium hydride, in a suitable reaction-inert solvent, e.g. tetrahydrofuran. 
Intermediates of formula (LXXI), wherein, in the definition of Q2, the carbon atom carrying the hydroxy, carries also at least one hydrogen, said HOxe2x80x94Q2 being represented by HOxe2x80x94Q3H, and said intermediates being represented by formula (LXXI-b), can be prepared by reducing an intermediate of formula (IX) with a suitable reducing agent, e.g. sodium borohydride, in a reaction-inert solvent, e.g. an alcohol. 
Intermediates of formula (VI) wherein, in the definition of Q2, R2 is C1-10alkyl substituted with N(P)2 and the carbon atom adjacent to the nitrogen atom carrying the R2 substituent carries also at least one hydrogen atom, said Q2 being represented by (P)2Nxe2x80x94C1-10alkyl-NHxe2x80x94Q2aH, and said intermediates being represented by formula (VI-a), can be prepared by reductive amination of an intermediate of formula (LXXVI) with an intermediate of formula (LXXVII) in the presence of a suitable reductive agent, such as hydrogen, and a suitable catalyst, such as palladium-on-charcoal, platinum-on-charcoal, and the like, and optionally in the presence of a suitable catalyst poison, such as a thiophene solution. A suitable solvent in this reaction is a reaction-inert solvent, such as an alcohol. 
Intermediates of formula (LXXVI) can be prepared by deprotecting an intermediate of formula (LXXVIII) in the presence of a suitable acid, such as hydrochloric acid and the like, in a suitable solvent, e.g. water. 
Intermediates of formula (IX) may be prepared by deprotecting an intermediate of formula (LXXIX) in the presence of a suitable acid, e.g. hydrochloric acid and the like. 
Intermediates of formula (LXXIX) can be prepared by reacting an intermediate of formula (LXXX) with an intermediate of formula (III) in the presence of a suitable base, e.g. dipotassium carbonate, in a suitable reaction-inert solvent, e.g. acetonitrile. 
Intermediates of formula (LXXX) wherein, in the definition of Q3, the X1 or X2 moiety of the radicals of formula (b-1) to (b-8) represent NH, said Q3 being represented by Q3xe2x80x2xe2x80x94NH, and said intermediates being represented by formula (LXXX-a), may be prepared by cyclizing an intermediate of formula (LXXXI) in the presence of mercury oxide and sulphur, in a suitable reaction-inert solvent, e.g. an alcohol. 
Intermediates of formula (LXXXI) can be prepared by reducing an intermediate of formula (LXXXII) in the presence of a suitable reducing agent, such as hydrogen, in the presence of a suitable catalyst, such as palladium-on-charcoal, platinum-on-charcoal and the like, in a suitable solvent, e.g. a mixture of ammonia in alcohol. Suitable alcohols are methanol, ethanol, 2-propanol and the like. 
Intermediates of formula (LXXXI) can be prepared by reacting an intermediate of formula (LXXXIII) with an intermediate of formula (LXXXIV) in a suitable reaction-inert solvent, e.g. ethanol. 
Intermediates of formula (IX), wherein, in the definition of Q3xe2x80x2, R2 comprises C1-10alkyl, said Q3 being represented by C1-10alkyl-Q1b, and said intermediates being represented by formula (IX-a), can be prepared by reacting a compound of formula (I-a-3) with a reagent of formula (LXXXV), wherein (Oxe2x95x90)C1-10alkyl represents a carbonyl derivative of C1-10alkyl and wherein W11 is a suitable leaving group, such as a halo atom, e.g. bromo, in a reaction-inert solvent, e.g. acetonitrile, in the presence of a suitable base, e.g. dipotassium carbonate. 
Intermediates of formula (X) wherein Q4 comprises C1-9alkyl, said Q4 being represented by C1-9alkyl-Q1b, and said intermediates being represented by formula (X-a), can be prepared by reacting a compound of formula (I-a-3) with a reagent of formula (LXXXVI) wherein W12 represents a suitable leaving group, such as a halo atom, e.g. chloro, in a reaction-inert solvent, e.g. 3-methyl-2-butanone, in the presence of a suitable base, e.g. dipotassium carbonate, sodium bicarbonate and the like. 
Intermediates of formula (X), wherein NCxe2x80x94Q4 represents NCxe2x80x94(C1-9alkyl)(R4)Nxe2x80x94C(xe2x95x90O)-Alk-X1, said intermediates being represented by formula (X-b), can be prepared by reacting an intermediate of formula (LXXXVII) with an intermediate of formula (LXXXVII) in the presence of di-1H-imidazol-2-yl-methanone, a suitable base, such as N,N-diethyl-ethanamine, and a suitable solvent, such as methylene chloride. 
Intermediates of formula (XI), wherein Q4xe2x80x2 represents Q1b, said intermediates being represented by formula (XI-a), can be prepared by reacting a compound of formula (I-a-3) with an intermediate of formula (LXXXIX), wherein W13 represents a suitable leaving group, such as a halo atom, e.g. chloro, in the presence of a suitable base, such as disodium carbonate, and in the presence of a suitable solvent, such as 3-methyl-2-butanone. 
Intermediates of formula (XIX) can be prepared by reacting an intermediate of formula (XC) with a suitable acid, such as hydrochloric acid. 
Pure stereochemically isomeric forms of the compounds of formula (I) may be obtained by the application of art-known procedures. Diastereomers may be separated by physical methods such as selective crystallization and chromatographic techniques, e.g., counter-current distribution, liquid chromatography and the like.
The compounds of formula (I) as prepared in the hereinabove described processes are generally racemic mixtures of enantiomers which can be separated from one another following art-known resolution procedures. The racemic compounds of formula (I) which are sufficiently basic or acidic may be converted into the corresponding diastereomeric salt forms by reaction with a suitable chiral acid, respectively chiral base. Said diastereomeric salt forms are subsequently separated, for example, by selective or fractional crystallization and the enantiomers are liberated therefrom by alkali or acid. An alternative manner of separating the enantiomeric forms of the compounds of formula (I) involves liquid chromatography, in particular liquid chromatography using a chiral stationary phase. Said pure stereochemically isomeric forms may also be derived from the corresponding pure stereochemically isomeric forms of the appropriate starting materials, provided that the reaction occurs stereospecifically. Preferably if a specific stereoisomer is desired, said compound will be synthesized by stereospecific methods of preparation. These methods will advantageously employ enantiomerically pure starting materials.
The compounds of formula (I) show antiviral properties. Viral infections treatable using the compounds and methods of the present invention include those infections brought on by ortho- and paramyxoviruses and in particular by human and bovine respiratory syncytial virus (RSV).
The in vitro antiviral activity against RSV of the present compounds was tested in a test as described in the experimental part of the description, and may also be demonstrated in a virus yield reduction assay. The in vivo antiviral activity against RSV of the present compounds may be demonstrated in a test model using cotton rats as described in Wyde et al. (Antiviral Research (1998), 38, 31-42).
Due to their antiviral properties, particularly their anti-RSV properties, the compounds of formula (I) or any subgroup thereof, their prodrugs, N-oxides, addition salts, quaternary amines, metal complexes and stereochemically isomeric forms, are useful in the treatment of individuals experiencing a viral infection, particularly a RSV infection, and for the prophylaxis of these infections. In general, the compounds of the present invention may be useful in the treatment of warm-blooded animals infected with viruses, in particular the respiratory syncytial virus.
The compounds of the present invention or any subgroup thereof may therefore be used as medicines. Said use as a medicine or method of treatment comprises the systemic administration to viral infected subjects or to subjects susceptible to viral infections of an amount effective to combat the conditions associated with the viral infection, in particular the RSV infection.
The present invention also relates to the use of the present compounds or any subgroup thereof in the manufacture of a medicament for the treatment or the prevention of viral infections, particularly RSV infection.
The compounds of the present invention or any subgroup thereof may be formulated into various pharmaceutical forms for administration purposes. As appropriate compositions there may be cited all compositions usually employed for systemically administering drugs. To prepare the pharmaceutical compositions of this invention, an effective amount of the particular compound, optionally in addition salt form or metal complex, as the active ingredient is combined in intimate admixture with a pharmaceutically acceptable carrier, which carrier may take a wide variety of forms depending on the form of preparation desired for administration. These pharmaceutical compositions are desirable in unitary dosage form suitable, particularly, for administration orally, rectally, percutaneously, or by parenteral injection. For example, in preparing the compositions in oral dosage form, any of the usual pharmaceutical media may be employed such as, for example, water, glycols, oils, alcohols and the like in the case of oral liquid preparations such as suspensions, syrups, elixirs, emulsions and solutions; or solid carriers such as starches, sugars, kaolin, lubricants, binders, disintegrating agents and the like in the case of powders, pills, capsules, and tablets. Because of their ease in administration, tablets and capsules represent the most advantageous oral dosage unit forms, in which case solid pharmaceutical carriers art obviously employed. For parenteral compositions, the carrier will usually comprise sterile water, at least in large part, though other ingredients, for example, to aid solubility, may be included. Injectable solutions, for example, may be prepared in which the carrier comprises saline solution, glucose solution or a mixture of saline and glucose solution. Injectable suspensions may also be prepared in which case appropriate liquid carriers, suspending agents and the like may be employed. Also included are solid form preparations which are intended to be converted, shortly before use, to liquid form preparations. In the compositions suitable for percutaneous administration the carrier optionally comprises a penetration enhancing agent and or a suitable wetting agent, optionally combined with suitable additives of any nature in minor proportions, which additives do not introduce a significant deleterious effect on the skin.
The compounds of the present invention may also be administered via oral inhalation or insufflation by means of methods and formulations employed in the art for administration via this way. Thus, in general the compounds of the present invention may be administered to the lungs in the form of a solution, a suspension or a dry powder, a solution being preferred. Any system developed for the delivery of solutions, suspensions or dry powders via oral inhalation or insufflation are suitable for the administration of the present compounds.
Thus, the present invention also provides a pharmaceutical composition adapted for administration by inhalation or insufflation through the mouth comprising a compound of formula (I) and a pharmaceutically acceptable carrier. Preferably, the compounds of the present invention are administered via inhalation of a solution in nebulized or aerosolized doses.
It is especially advantageous to formulate the aforementioned pharmaceutical compositions in unit dosage form for ease of administration and uniformity of dosage. Unit dosage form as used herein refers to physically discrete units suitable as unitary dosages, each unit containing a predetermined quantity of active ingredient calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier. Examples of such unit dosage forms are tablets (including scored or coated tablets), capsules, pills, suppositories, powder packets, wafers, injectable solutions or suspensions and the like, and segregated multiples thereof.
In general it is contemplated that an antivirally effective daily amount would be from 0.01 mg/kg to 500 mg/kg body weight, more preferably from 0.1 mg/kg to 50 mg/kg body weight. It may be appropriate to administer the required dose as two, three, four or more sub-doses at appropriate intervals throughout the day. Said sub-doses may be formulated as unit dosage forms, for example, containing 1 to 1000 mg, and in particular 5 to 200 mg of active ingredient per unit dosage form.
The exact dosage and frequency of administration depends on the particular compound of formula (I) used, the particular condition being treated, the severity of the condition being treated, the age, weight, sex, extent of disorder and general physical condition of the particular patient as well as other medication the individual may be taking, as is well known to those skilled in the art. Furthermore, it is evident that said effective daily amount may be lowered or increased depending on the response of the treated subject and/or depending on the evaluation of the physician prescribing the compounds of the instant invention. The effective daily amount ranges mentioned hereinabove are therefore only guidelines.
Also, the combination of another antiviral agent and a compound of formula (I) can be used as a medicine. Thus, the present invention also relates to a product containing (a) a compound of formula (I), and (b) another antiviral compound, as a combined preparation for simultaneous, separate or sequential use in antiviral treatment. The different drugs may be combined in a single preparation together with pharmaceutically acceptable carriers. For instance, the compounds of the present invention may be combined with interferon-beta or tumor necrosis factor-alpha in order to treat or prevent RSV infections.
The following examples are intended to illustrate the present invention.
A. Preparation of the Intermediate Compounds